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In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 μM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising.

Original publication

DOI

10.1016/j.ejmech.2016.07.042

Type

Journal article

Journal

Eur J Med Chem

Publication Date

10/11/2016

Volume

123

Pages

407 - 418

Keywords

Apoptosis, Cell cycle arrest, Chalcogen, Cytotoxicity, Selenium, Antineoplastic Agents, Cell Cycle Checkpoints, Cell Death, Cell Line, Tumor, Cell Proliferation, Chalcogens, Drug Screening Assays, Antitumor, Heterocyclic Compounds, Humans, Structure-Activity Relationship